Alzheimer's disease (AD), also known simply as Alzheimer's, is a neurodegenerative disease that, in its most common form, is found in people over age 65. Approximately 24 million people worldwide have dementia, of which the majority (˜60%) is due to Alzheimer's (Ferri C. P. et al. (2005) Lancet 366(9503):2112-2117). More than 5 million Americans are estimated to have Alzheimer's disease, and it is projected that this number will increase to 14.3 million by mid-century, representing a 350 percent increase from 2000.
The ultimate cause of Alzheimer's is unknown. Characteristic clinical symptoms of Alzheimer's disease include progressive cognitive deterioration, declining ability to participate in daily activities, neuropsychiatric symptoms, and behavioral changes. Plaques containing misfolded proteins, called beta amyloids, form in the brain many years before the clinical signs of Alzheimer's are observed. Together, these plaques and neurofibrillary tangles form the pathological hallmarks of the disease. These features can only be discovered at autopsy and help to confirm the clinical diagnosis.
The first readily identifiable symptoms of Alzheimer's disease are usually short-term memory loss and visual-spatial confusion. These initial symptoms progress from seemingly simple and often fluctuating forgetfulness and difficulty orienting oneself, to a more pervasive loss of short-term memory and difficulty navigating through familiar areas such as one's neighborhood, and ultimately progressing to loss of recognition of objects and persons. Aphasia, disorientation, and disinhibition often accompany the loss of memory. In later stages of the disease patients experience deterioration of musculature and mobility, leading to bedfastness, inability to feed oneself, and incontinence. While the onset, advancement, and severity of these conditions are highly variable in nature, the types of symptoms are common, including behavioral changes (e.g. depression and agitation), and loss of the ability to carry out basic daily activities (e.g. grooming, dressing, walking, etc.).
There is currently no cure for Alzheimer's disease. Current pharmacological treatments for mild to moderate AD include selective acetylcholinesterase inhibitors, such as Donepezil, and uncompetitive NMDA receptor antagonists, such as Memantine (Reisberg 2006, Feldman 2004). Clinical studies of these treatments have demonstrated efficacy relative to their mean rate of decline with a placebo (Johannsen 2006); however, in addition to a host of adverse events that accompany these treatments, there still remains a steady decline in performance on neuropsychological exams and caregiver's assessments over the course of these studies. Moreover, the average monthly costs of these treatments can exceed $1000 (Plosker 2005, Feldman 2004). At over $100 billion per year, AD is the third most costly disease in the U.S., after heart disease and cancer. There is therefore a current and growing need for an inexpensive, over-the-counter formulation that can improve symptoms commonly associated with Alzheimer's disease.
Behavioral and psychological symptoms of dementia (BPSD) often accompany Alzheimer's Disease, and generally worsen as the illness advances. The presence of non-cognitive behavioral symptoms such as mood disorders, psychosis, and aggressive behavior, can be equally or more taxing to caregivers as cognitive decline, and is often a deciding factor in the decision to institutionalize a patient. Aggressive behavior has been correlated with genetic risk factors, particularly the presence of the E4 allele of ApoE, known to confer considerable risk for onset and rapid progression of AD. Mice expressing the human ApoE4 allele have served as a useful animal model of AD. Cholinergic deficits have been linked to both cognitive decline and BPSD, in part by exacerbating vulnerability to the effects of other neurochemical imbalances. The highest level of cholinergic innervation is received by the limbic system, an area of the cortex affiliated with BPSD. Treatments for behavioral symptoms have traditionally included antipsychotic medications and benzodiazepines. These medications are, however, prescribed with caution due to the increased susceptibility of the elderly to a host of adverse side effects. Alternative treatments that are effective in treating the behavioral symptoms of AD are therefore highly desirable.
Poor nutrition has been shown to accelerate many symptoms associated with AD. For example, folate deficiency increases neuronal oxidative stress, in part by increasing levels of the neurotoxin homocysteine, which is related to the progression and severity of AD. Studies described herein demonstrate that folate deprivation potentiates at least 7 additional risk factors for AD; these include potentiation of genetic risk factors (presenilin-1 (PS-1) and ApoE deficiency), increased generation of the neurotoxic peptide amyloid-Beta and increased activity of the enzyme responsible for its generation (gamma secretase), an increase in hyperphosphorylation of tau (the precursor of neurofibrillary tangles) and a decline in the neurotransmitter acetylcholine, leading to impaired cognitive performance and increased aggression. As such, the development of a nutriceutical formulation that improves symptoms and slows the progression of AD would provide a safe and cost-effective addition to current therapeutic strategies used to manage AD.
Given that AD is the most common form of dementia to afflict our rapidly aging society, there is a drive to not only treat patients diagnosed with AD, but also to initiate preventative measures to slow or prevent the onset of the disease (Mattson 2004, Post 1999). While attention has recently been given to pre-symptomatic AD detection, this attention has been devoted to defining and targeting the high-risk population. Although this is a logical approach, preventative measures for all aging individuals should be made, as the elderly is the fastest growing segment of the population. A nutriceutical formulation that is beneficial for patients with AD may additionally be useful as a preventative measure, and would be safe for administration to normal adults. Such a nutriceutical formulation may also be valuable for normal adults unaffected by AD who are nonetheless seeking to improve cognitive performance, improve mood, reduce depression, and reduce aggression.